DESCRIPTION: Cytokines produced by CD4+ T lymphocytes play essential roles in host adaptive immune responses and are involved in the development of allergic diseases including asthma. Our understanding of the pathways regulating cytokine production in CD4+ T lymphocytes remains incomplete. We have identified a novel pathway regulating cytokine production in CD4+ T cells using molecules that are thought to be primarily involved in neuronal cell function and pathogenesis of Alzheimer's disease. We show that CD4+ T cells lacking the extracellular matrix (ECM) protein F-spondin or its receptor apoE receptor 2 (ApoER2) exhibit defective cytokine production, and asthma development is attenuated in mice lacking F-spondin. Our overall hypothesis is that F-spondin and its receptors ApoER2 and amyloid-2 precursor protein (APP) constitute a novel ligand-receptor pairs whose interaction on the CD4+ T cell surface provides a critical signal to initiate cytokine production. To test this hypothesis, we propose two specific aims: 1. To establish the mechanisms by which F-spondin regulates CD4+ T lymphocyte cytokine production. 2. To examine the signaling pathway mediated by ApoER2 and APP in CD4+ T lymphocyte cytokine production. Results from these studies will not only provide important mechanistic insights into the regulation of CD4+ T lymphocyte cytokine production and asthma development, but also may lead to discoveries of novel drug targets for asthma treatment. Given the current effort by industry and academia to develop Alzheimer's disease treatments, our proposed research may be able to redirect the drugs developed for Alzheimer's disease into asthma treatment. Project Narrative Cytokines produced by CD4+ T lymphocytes are involved in the development of allergic diseases including asthma. Our understanding of the pathways regulating cytokine production and asthma development remains incomplete. Investigation of the pathways regulating cytokine production and asthma development will lead to new discoveries that will help drug designs for asthma treatment. Our recent work has identified a novel pathway regulating cytokine production in CD4+ T cells and asthma development in mice by molecules that are thought to be primarily involved in neuronal cell function and pathogenesis of Alzheimer's disease. Given the current effort in the development of Alzheimer's disease treatment by industry and academia, our proposed research may be able to redirect the drugs developed for Alzheimer's disease into asthma treatment.